Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[C:16]2=[N:15][C:14]=1[CH3:28].[CH2:29]1[CH2:33]OC[CH2:30]1.C([Mg]Br)CC.C(OCC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([C:22]([OH:26])([CH2:30][CH2:29][CH3:33])[CH2:23][CH2:24][CH3:25])[C:16]2=[N:15][C:14]=1[CH3:28]
Reactant: CCCC(=O)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Reactant: C1CCOC1
Agent: CCC[Mg]Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCC(O)(CCC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 1-{3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazin-8-yl}-butan-1-one (0.15 g, 0.36 mmol) and THF (5 mL) is cooled to 0° C., and a 2.0 M propyl magnesium bromide solution in diethylether (0.22 mL, 0.43 mmol) is added. The reaction is warmed to ambient temperature, diluted with ethyl acetate (30 mL), and washed with a sat. NH4Cl solution (30 mL). The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified by ISCO flash chromatography (20%-40% EtOAc gradient) to furnish the title compound (0.016 g, 0.017 mmol, 47%). 1H-NMR (CDCl3), δ 0.90 (t, J=7.4 Hz, 6H), 1.12-1.29 (m, 2H), 1.37-1.54 (m, 2H), 1.86-2.04 (m, 4H), 2.50 (s, 3H), 2.54 (s, 3H), 4.15 (s, 3H), 6.11 (bs, 1H), 6.73 (s, 1H), 7.48 (s, 1H), 7.90 (s, 1H) ppm. LC/MS (m/z): calcd. for C22H27ClN6OS (M+H)+: 459.2; found: 459.3.
Reaction SMILES: O=S(Cl)[Cl:3].[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C@@H:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([OH:23])=O)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1>>[ClH:3].[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C@@H:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([Cl:3])=[O:23])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1
Reactant: CN1CCN([C@H]2CCc3cc(C(=O)O)ccc32)CC1
Reactant: O=S(Cl)Cl
Product: CN1CCN([C@H]2CCc3cc(C(=O)Cl)ccc32)CC1
Product: Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
SOCl2 (2.5 L) was added to a 5 L three-neck flask. (1S)-1-(4-Methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-carboxylic acid (1289 g, the actual maximum content of 583 g, equivalent to 2.235 mol) was then added in batches within 1 hour. The solution was heated under reflux overnight and then cooled to room temperature. Most of SOCl2 was removed using rotary evaporator. After ethyl acetate (1.5 L) was added, the solution was cooled to 0° C., filtered with suction to obtain the white solid which was then dried in vacuum to get the title compound (about 1325 g, 100% yield).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][C:8]([OH:17])=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][Cl:24])[CH3:20].OC1C=CC2C(=O)C3C(=CC=C(O)C=3)C(=O)C=2C=1.[CH:45]([N:48]([CH:52](C)[CH3:53])[CH2:49][CH2:50][Cl:51])(C)[CH3:46]>>[ClH:24].[ClH:51].[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][C:8]([O:17][CH2:46][CH2:45][N:48]([CH2:52][CH3:53])[CH2:49][CH3:50])=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1)[CH3:20]
Reactant: CCN(CC)CCCl
Reactant: O=C1c2ccc(O)cc2C(=O)c2cc(O)ccc21
Reactant: CC(C)N(CCCl)C(C)C
Agent: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Product: CCN(CC)CCOc1ccc2c(c1)C(=O)c1cc(OCCN(CC)CC)ccc1C2=O
Product: Cl

Procedure:
When in the procedure of Example 22, 2,7-dihydroxyanthraquinone and 2-diethylaminoethyl chloride are respectively substituted for 2,6-dihydroxyanthraquinone and 2-diisopropylaminoethyl chloride, 2,7-bis(2-diethylaminoethoxy)anthraquinone dihydrochloride is obtained. M.P. 232°-234°C (dec.).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.[H-].[Na+].[O:25]1[CH2:29][CH2:28]OS1(=O)=O.O>CN(C)C=O>[OH:25][CH2:29][CH2:28][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: O=S1(=O)OCCO1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.01 g of tert-butyl 3-hydroxy-4(4-methoxyphenyl)piperidine-1-carboxylate in 40 ml of N,N-dimethylformamide is added at 0° C. to the suspension of 0.26 g of sodium hydride dispersion (60%) in 40 ml of N,N-dimethylformamide. After 30 minutes, the reaction mixture is admixed with 0.83 g of [1,3,2]dioxathiolane 2,2-dioxide and stirred at room temperature over 18 hours. The reaction mixture is cooled to 0° C., admixed with water and concentrated by evaporation. The residue is stirred in a 1:10 mixture of 0.1 M H2SO4/dioxane at 50° C. over 60 hours, neutralized with saturated aqueous sodium hydrogencarbonate solution and concentrated by evaporation. The residue is dissolved in ethyl acetate, washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:1 EtOAc-heptane); Rt=4.24.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([CH:46]2[CH2:48][CH2:47]2)[N:18](COCC[Si](C)(C)C)[C:19]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[CH3:29])[N:21]=1.Cl>CCO>[NH2:30][C@@H:28]([CH3:29])[CH2:27][NH:26][C:22]1[N:21]=[C:20]([C:19]2[NH:18][C:17]([CH:46]3[CH2:48][CH2:47]3)=[N:16][C:15]=2[C:3]2[C:2]([Cl:1])=[C:7]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)n(COCC[Si](C)(C)C)c2-c2ccnc(NC[C@H](C)NC(=O)OC(C)(C)C)n2)c1Cl
Agent: Cl
Solvent: CCO
Product: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)[nH]c2-c2ccnc(NC[C@H](C)N)n2)c1Cl
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 107.1 %

Procedure:
A solution of (S)-tert-butyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (116 mg, 0.14 mmol) in EtOH (2 mL) was treated with aqueous 6.0 N HCl solution (0.8 mL, 4.8 mmol) and the resulting reaction was heated to 60° C. for 30 minutes, then at room temperature for 40 minutes. The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. Further drying under high vacuum afforded (S)—N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide (80 mg, 0.15 mmol) as the HCl salt (4A-2) which was used without further purification: LCMS(m/z) 490.2 (MH+), tR=0.48 minute. To a mixture of (S)—N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide in THF-water (1:1, 2 mL) at 0° C. was added solid NaHCO3 (137 mg, 1.6 mmol) and the resulting mixture was stirred for 5 minutes. Methyl chloroformate (14 μL, 0.18 mmol) was added and the reaction mixture was stirred at 0° C. for 15 minutes. The reaction was diluted with water and extracted with EtOAc (2×). The combined organic portions were washed with water, brine, dried (Na2SO4), and concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC. Product fractions were combined and lypholized to give (S)-methyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (19.9 mg) as the TFA salt (4A-3): LCMS(m/z) 548.0 (MH+), tR=0.61 minute, 1H NMR (400 MHz, CD3OD) δ 1.04 (t, J=7.4 Hz, 3H) 1.14 (d, J=6.6 Hz, 3H) 1.27 (t, J=4.5 Hz, 2H) 1.34-1.44 (m, 2H) 1.80-1.95 (m, 2H) 3.14-3.21 (m, 2H) 3.67 (br s, 3H) 3.97 (br s, 1H) 6.40 (br s, 1H) 7.45 (d, 7.0 Hz, 1H) 7.54 (m, 1H) 7.84 (d, J=7.4 Hz, 1H) 8.13 (d, J=5.1 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([NH2:22])[CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:21])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1>[CH2:34]([O:33][C:31]([NH:22][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[CH:13][CH:12]=1)=[O:32])[CH3:35]
Reactant: Cc1ccc(OCCC(N)c2ccccc2)c2ccccc12
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(CCOc1ccc(C)c2ccccc12)c1ccccc1
Temperature: 25 °C
Yield: 103.3 %

Procedure:
A solution of 2.12 g (7.3 mmol) of 1-phenyl-3-(4-methyl-1-naphthalenyloxy)propanamine, 1.12 ml (8.0 mmol) of triethylamine and 100 ml of THF was cooled to approximately 0° C. under a nitrogen atmosphere. To the mixture was added 0.766 ml (8.0 mmol) of ethyl chloroformate dropwise. The resulting mixture was stirred at room temperature for approximately five and one-half hours and concentrated under vacuum. The residue was dissolved in diethyl ether, toluene and water. The mixture was extracted with diethyl ether. The organic extracts were combined, washed with water, 2N hydrochloric acid, water, 1N sodium hydroxide water, and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum to provide 2.74 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[N:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:1]2[CH:2]([C:10]3[C:11]([O:18][CH3:19])=[N:12][CH:13]=[N:14][C:15]=3[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:21]=1
Reactant: COC(=O)CCCC(N)c1c(OC)ncnc1OC
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: COc1ncnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(4,6-dimethoxypyrimidin-5-yl)pentanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 403.96 g/mol.
Reaction SMILES: [C:1]12(CO)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.[CH3:18]C1C(B2OC(C)(C)C(C)(C)O2)=C(C)NN=1>>[CH:1]12[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH:8]1[CH2:18][N:13]1[CH:17]=[CH:16][CH:15]=[N:14]1)[CH2:10]2
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: c1cn[nH]c1
Product: c1cnn(CC2C3CC4CC(C3)CC2C4)c1

Procedure:
The title compound was prepared by substituting EXAMPLE 10A for 1-adamantanemethanol and pyrazole for 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 2A.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[S:13][C:12]([C:14]([O:16]CC)=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH2:36])[NH:34][N:35]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH:36][C:14]([C:12]3[S:13][C:9]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:10][CH:11]=3)=[O:16])[NH:34][N:35]=2)[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCCN(C)CC2)s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
Ethyl 5-(4-methyl-1,4-diazepan-1-yl)thiophene-2-carboxylate (0.201 g, 0.75 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.185 g, 0.75 mmol) in toluene (10 mL) were stirred at 20° C. and a 2M solution of trimethylaluminium in toluene (0.938 mL, 1.88 mmol) was added drop-wise. The reaction stirred under nitrogen at 60° C. for 18 h. The reaction mixture was cooled and quenched by pouring into methanol (50 ml), acidified with few drops of 2N hydrochloric acid. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.162 g, 46.0%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][C:27]([NH2:29])=[O:28]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:23][O:24][CH2:26][C:27]([NH2:29])=[O:28])[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@](CO)(c2ccc(Cl)c(Cl)c2)CC1
Reactant: NC(=O)CBr
Product: Cl
Product: NC(=O)COC[C@]1(c2ccc(Cl)c(Cl)c2)CCNCCO1

Procedure:
Using tert-butyl (7R)-7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate and 2-bromoacetamide, and by a method similar to that of Example 363, step B and Example 39, step B, the title compound was obtained.
Reaction SMILES: [C:1]([CH2:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[N+:30]([O-])=O)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O.C(Cl)Cl.CCOC(C)=O.[Fe]>[NH2:2][C:1]1[CH2:3][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[N:30]=1
Reactant: CCOC(=O)/C(=C/c1ccc(-c2ccc(C(=O)N3CCCC3)cc2)cc1[N+](=O)[O-])CC#N
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(N)C1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of the crude (E)-ethyl 2-(cyanomethyl)-3-(3-nitro-4′-(pyrrolidine-1-carbonyl)biphenyl-4-yl)acrylate in AcOH (650 mL) was added iron (29.1 g, 521 mmol) at room temperature. The resulting mixture was heated at 85° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with CH2Cl2 (250 mL). The solids were filtered off and washed with CH2Cl2 (200 mL). The filtrate was concentrated under reduced pressure to give the crude material that was diluted with CH2Cl2 (250 mL) again. To this mixture was slowly added sat'd aq Na2CO3 (˜330 mL) with vigorous stirring until it became basic (pH ˜9-10). The resulting mixture was filtered off and washed with CH2Cl2 (˜250 mL). The aqueous layer was separated and extracted with CH2Cl2 (2×150 mL). The combined organic layers were washed with brine, dried over MgSO4, and filtered to give the crude material that was diluted with EtOAc (70 mL). The mixture was kept for 16 h at room temperature. The suspension was filtered. The solids filtered off were washed with EtOAc (100 mL) to give the crude product that was washed with a small amount of CH2Cl2 to afford 20 g (62% based on 95% purity) of (1E,4E)-ethyl 2-amino-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([NH:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.CN(C)C=O.[OH-].[K+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>CO>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][N:13]1[C:14](=[O:15])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12]
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: BrCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Reaction time: 1 h

Procedure:
100 g. (0.5 mole) of 1,8-naphthalimide is suspended in 2100 ml. of dimethylformamide and the mixture is heated to 90° to form a complete solution. A solution of 36.3 g. (0.55 mole) of potassium hydroxide (85%) in 100 ml. of methanol is added resulting in the immediate formation of a yellow precipitate. The resulting mixture is stirred for one hour at 90° and cooled to 25°. 245 g. (1.0 mole) of 1,4-dibromobutane is added and the mixture is again heated to 90° and stirred for an additional hour. A precipitate remains in the mixture but is more granular than the initial material. The reaction mixture is cooled and the precipitate filtered off. The solvent is removed under vacuum and the residue is diluted with 500 ml. of hexane immediately precipitating crude 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione. The precipitate is filtered off, washed with fresh hexane and dried for 2 hours at 50° (0.1 mm.) to yield 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione. An analytically pure sample is prepared by dissolving the above product in hot 95% ethanol and recrystallizing by allowing the solution to cool to 25°. The resulting precipitate is dried for 2 hours at 50° (0.1 mm.) to yield pure 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, m.p. 113°-115°.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[H-].[Na+].Br[C:13]1[C:14]([F:24])=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[CH:18][CH:17]=[CH:16]2.Cl.O1CCO[CH2:28][CH2:27]1>O.COC(C)(C)C>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:13]1[C:14]([F:24])=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[CH:18][CH:17]=[CH:16]2)[C:3]([O:5][CH2:27][CH3:28])=[O:4])[CH3:9]
Reactant: C1COCCO1
Reactant: Fc1cc2ncccc2c(F)c1Br
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cc2ncccc2c1F
Yield: 35.4 %

Procedure:
Ethyl malonate (9.28 g, 8.8 mL, 58.0 mmol) was added dropwise to a mixture of sodium hydride (60 percent in mineral oil, 2.32 g, 58.0 mmol) in 1,4-dioxane (29 mL) at 60° C. CuBr (4.176 g, 29.0 mmol) and 6-bromo-5,7-difluoro-quinoline (7.07 g, 29.0 mmol) were then added and the mixture heated to reflux for 16 h. After such time concentrated hydrochloric acid was added under ice-cooling and then tert-butyl methyl ether and water were added. The separated organic layer was washed with (10%) hydrochloric acid and water sequentially. Dried over sodium sulfate and concentrated. The residue was purified by column chromatography to afford the title compound (3.13 g, 35.4%).
Reaction SMILES: ClCCl.C(#N)C.[CH2:7]([O:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH:19]([CH:22]3[CH2:27][O:26][C:25]([CH2:29][CH2:30][CH3:31])(O)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[C:12]([F:34])[C:11]=1[F:35])[CH3:8].C([SiH](CC)CC)C>O>[CH2:7]([O:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH:19]([CH:22]3[CH2:27][O:26][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[C:12]([F:34])[C:11]=1[F:35])[CH3:8]
Reactant: CCCC1(O)CCC(C2CCC(COc3ccc(OCC)c(F)c3F)CC2)CO1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCCC1CCC(C2CCC(COc3ccc(OCC)c(F)c3F)CC2)CO1
Yield: 57.8 %

Procedure:
In a reactor under nitrogen atmosphere, 100 mL of dichloromethane and 20 mL of acetonitrile were added to 3.6 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]2-propyltetrahydropyran-2-ol obtained in the thirteenth step, and the mixture was cooled to −20° C., to which 2.7 mL of triethylsilane was added dropwise, and subsequently 1.5 mL of boron trifluoride diethyl ether complex was added dropwise. The temperature of the reaction solution was increased to 0° C., to which 50 mL of iced water was added, followed by extracting three times with 30 mL of diethyl ether. The mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and recrystallization to provide 2.0 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]2-propyltetrahydropyran.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:30]1([CH3:42])[CH:35]=[CH:34][C:33]([S:36]([N:39]=[C:40]=[O:41])(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:42][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)=[O:41])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1
Yield: 87 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) in 15 ml of methylene chloride under nitrogen is added dropwise a solution of p-tolylsulfonyl-isocyanate in 10 ml of methylene chloride over a period of 10 minutes. After complete addition, the resultant suspension is stirred at room temperature for 1 hour. The white solid is filtered, washed with more methylene chloride, and dried giving 2.6 g (87%) of N-[(4-methylphenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine-1-carboxamide of melting point 253°-255° C. Infrared and mass spectra are consistent with the assigned structure.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:8][N:9]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1ccccc1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2-c1ccccc1
Yield: 99.1 %

Procedure:
A solution of 4-methoxy-1-phenyl-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (83 mg), tetrakis(triphenylphosphine)palladium(0) (31.0 mg) and 2M aqueous sodium carbonate solution (1.0 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (101 mg).